Association of Statins With Functional Outcome and 30-Day Mortality in Patients With Intracerebral Hemorrhage

Aim The effect of statins is well established in cardiac and cerebrovascular diseases. However, its impact on intracerebral hemorrhage (ICH) is unclear. We aim to identify an association of pre-ICH statin treatment and statin use during admission for ICH with functional outcome at discharge and 30-day mortality. Material and methods A retrospective cohort study was held in patients with ICH admitted to our stroke unit over a year period. Demographic characteristics, risk factors and cardiovascular diseases, Glasgow Coma Scale (GCS), National Institutes of Health Stroke Score (NIHSS), systolic blood pressure (SBP) at admission, cholesterol levels and radiologic findings were analyzed to explore the association between pre-ICH and inpatient statin use with outcomes. The primary endpoint was functional outcome defined as modified Rankin Score (mRS) at discharge and 30-day mortality. We performed a univariate analysis and the variables with statistical significance were included in a multivariate analysis to control for confounding covariates. Results The study included 78 patients, 33 (42.31%) had previous statin intake history, of which 13 (39.39%) maintained statin intake during hospitalization. Regarding functional outcome we did not report a statistically significant difference between groups. In the “pre-ICH statin use” group a decreased 30-day mortality (6.06%, p = 0.009) was observed. In this group it was also noted higher antiplatelet medication use (33.33%, p = 0.006), higher GCS at admission (13-15: 84.38%, p = 0.018) and deep ICH (81.82%, p = 0.030). However, 30-day mortality had no impact in multivariate regression (Odds ratio (OR) 4.535, 95% Confidence Interval (CI) = 0.786-26.173, p = 0.091). In the group that maintained statin treatment during hospitalization no deaths were registered (p = 0.020) and there was no association with functional status. Multivariate regression analysis was not performed due to sample size. Conclusion The only association demonstrated in this study was lower 30-day mortality with pre-ICH statin use and continued statin treatment during admission. However, this was not confirmed by multivariate regression analysis. There were no differences between groups concerning cholesterol values, results that can be explained by the pleiotropic and immunomodulatory effect of statins. However, prospective studies are needed to prove the benefit of the statins in ICH.


Introduction
Intracerebral hemorrhage (ICH) is the second most common cause of stroke (10-15% of all strokes) [1]. The 30-day mortality ranges from 35% to 52% and half of these deaths occur within the first two days [2]. Given the morbidity and mortality associated with ICH, assessment of therapies with neuroprotective effects is of increasing interest.
Statins inhibit, in a reversible way, the HMG-CoA reductase, which is the limiting step in cholesterol synthesis [3]. This mechanism is responsible for dyslipidemia treatment and the reduction of primary and secondary cardiovascular events [3]. Despite these benefits, a post hoc analysis from Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed a three-fold increase of recurrent ICH in patients treated with statin [4]. There are data regarding the contribution of low levels of serum cholesterol to the cerebrovascular endothelium fragility and statin treatment to the decreased platelet aggregation and thrombogenesis. Both mechanisms could promote hematoma expansion, increase the risk for recurrent hemorrhage, and aggravate ICH mortality or functional outcomes [5][6].
Statins also have pleotropic effects, like anti-inflammatory, antithrombotic, antioxidative, and neuroprotective. These are being demonstrated in animal and human models [3]. In this regard, a few studies reported that statin use was associated with reduced mortality and improved functional outcome after ICH. There is a paucity of data regarding beneficial impact of stating in acute ICH.
Therefore, we set out to investigate the association between pre-ICH statin treatment and statin use during admission with functional outcomes and 30-day mortality.
This article was previously presented as a meeting poster at the 26th National Congress of Internal Medicine of the Portuguese Society of Internal Medicine on August 27, 2020.

Materials And Methods
We performed a retrospective study on primary ICH patients admitted in a single-center stroke unit, from 1st of June 2018 to the 31st of May 2019. All patients with a baseline admission computerized tomography (CT) scan and medical records of pre-ICH statin use were eligible. Individuals with no inclusion criteria, diagnosed with subdural or subarachnoid hemorrhage, ischemic stroke with hemorrhagic transformation, traumatic hemorrhage, bleeding cerebral tumor and cerebral vascular malformation were excluded.
Statin use was further dichotomized into prior-ICH use and no use and continued or discontinued during hospitalization.
The primary endpoints were the effect of statin use on functional status at discharge and 30-day mortality in ICH patients. Functional status was defined by modified Rankin Score (mRS) considering good outcome 0-2 and bad outcome 3-6.
Statistical analysis was performed in two steps. First, a univariate analysis was done. Statistically significant results were used in a multivariate regression analysis to explore the effect of pre-ICH statin use and statin continuation during hospitalization in functional outcome at discharge and 30-day mortality.
Categorical variables are presented as frequencies and percentages, and continuous variables as median and interquartile range due to skewed distributions or mean and standard deviation. Normal distribution was checked using Shapiro-Wilk test. Categorical variables were compared with chi-square test and continuous variables were compared with Mann-Whitney or t-student in non-or parametric test respectively. All reported "p" values are two-tailed, with a "p" value of 0.05 indicating statistical significance (CI 95%). Analyses were performed with the use of "Statistical Package for the Social Sciences" (SPSS) version 26 (IBM Corp., Armonk, NY).

Results
Eighty-three ICH patients were admitted in the stroke unit over the study period. Five cases were excluded due to missing data about pre-ICH statin use.
Our final study population included 78 patients, of which 57.70% (45) were male. Median age was 76.00+/-14.00 years, a median length of stay in the stroke unit was 4.24+/-2.35 days and 17.35+/-20.74 days in other medical wards. Overall, 11 patients (14.10%) had good functional outcome and 16 (20.51%) patients died during the first 30 days after ICH, of which 10 (62.50%) occurred in stroke unit and six (37.50%) in other wards.

Discussion
In our population, pre-ICH statin treatment and statin use during hospitalization was not associated with functional outcomes at discharge. A trend associating statin use pre-ICH or during admission with decreased 30-day mortality was noted with statistical significance but with no impact after adjusting for other potential confounders.
The findings of our study shed light on the contradictory data about the influence of statins on outcomes after ICH. This is a complex disease and involves several factors that independently or co-dependently affect the outcome of these patients.
In 2004, SPARCL trial found out that treatment with atorvastatin was independently associated with an increased risk of hemorrhagic stroke (hazard ratio, 1.68; 95% CI, 1.09-2.59) [4]. However, this trial enrolled patients with prior ischemic stroke and with probable secondary microvascular injury [3].
There are studies that reported increased rates of ICH and ICH-related mortality in patients with low cholesterol levels [7] and that low LDL was an important predictor of hematoma growth [6]. It has been hypothesized that cholesterol may be important for cerebrovascular wall integrity and that low levels may increase the risk of vessel rupture and higher fibrinolytic activity [8]. Statins are lipid-lowering therapy so we should expect a bad outcome in patients with pre-ICH statin use [7].
In our study, the results were independent of cholesterol levels. It was also noted an association between pre-ICH statin use and better GCS at admission. Hence, the clinical benefit may not be limited to the lipidlowering properties of statins but also derived from other "pleiotropic" effects [7]. In animal experiments it has been possible to demonstrate the capacity of statins to improve ICH mortality by the promotion of neuronal plasticity and the limitation of damage in the boundary tissue [9], the increase of cerebral perfusion (mediated via increased endothelial nitric oxide secretion resulting in vasodilatation), the antiinflammatory proprieties, the improvement of angiogenesis and neurogenesis after ischemic injury. There is also evidence that statin discontinuation could lead to a rebound effect resulting in oxidative stress and vascular disfunction [10].
Supporting these findings, many observational studies in humans were performed, but with contradictory findings ( Table 4). In 2007, Naval et al.'s study was the first retrospective study that reported the benefit of pre-ICH statins treatment in humans by reducing early absolute edema volume and decreasing 30-day mortality (OR 0.080, p = 0.050), with no effect in functional outcomes at discharge [11]. FitzMaurice et al. found no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P 0.84) or mortality (46% versus 45%, P 0.93) and ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34-1.99, P 0.66) [11]. However cholesterol and triglycerides levels were not reported in any group, and medical comorbidity was more common in statin pretreated patients than in the non-pretreated group. Eichel et al. found that despite having significantly smaller haematomas, patients that were using statins did not have better neurological or functional outcomes at 90-day post-ICH [12]. Statin users more often had existing co-morbidities that adversely affect outcomes. This data points to the fact that statin users represent a generally more impaired population, and that these comorbidities can counteract the possible beneficial effects of statin use. Flint   patients) and outcomes. Only two prospective studies were performed, and both did not observe any association between pre-ICH statin use and 30-day mortality.
A few limitations to our study should be pointed out. This is an observational retrospective study although data was collected prospectively. It is possible that unmeasured or unknown confounders may influence the results. However, multiple regression helped to reduce this potential bias. We had a small sample size which could decrease the power of our study and make it difficult to test whether any particular statin or dose had superior effects. There was a lack of information regarding some variables like BMI (n = 34), lipidic profile at admission (n = 43-46), NIHSS at admission (n = 40) and mRS at discharge (n = 45). The later was a limitation to investigate the association between pre-ICH statin use and continuation during hospitalization and functional outcome at discharge. Also, clinical outcomes (mRS and mortality) were evaluated at discharge and not in a prolonged subacute time frame to maximize clinical recovery after ICH. Nevertheless, we acknowledge that neurological recovery following stroke may take place over longer periods of time and the variability in the time period following ICH that these patients were discharged might affect the data assessing functional outcomes.

Conclusions
In our study, pre-ICH statin use or continued treatment during admission was not associated with improved functional status. However, an association between these groups and decreased 30-day mortality was reported. These findings did not persist after adjusting for other variables.
Preclinical and clinical studies support the potential neuroprotective and recovery enhancement effects afforded by statins in the setting of acute ICH. There are conflicting data influenced due to heterogeneity of retrospective studies and absence of large prospective trials evaluating the safety and efficacy of statin therapy in ICH. Considering that the interpretations of our results are restricted by several limitations, future studies considering the impact of statins on mortality and functional outcomes are needed.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.